Methods and Compositions for the Delivery of a Therapeutic Agent

ABSTRACT

The present invention provides a liquid pharmaceutical composition comprising a therapeutic agent and an alkoxy-polyethylene glycol, for example, methoxy-polyethylene glycol, for administration of the therapeutic agent to the mammal. The compositions can be applied to a membrane, for example, a nasal membrane during intranasal administration. The invention also provides methods of administering such compositions to a mammal.

RELATED APPLICATIONS

This application claims the benefit of and priority to Icelandic PatentApplication Serial No. 8593/2007, filed Jan. 19, 2007, the entiredisclosure of which is incorporated by reference herein for allpurposes.

FIELD OF THE INVENTION

This invention relates generally to compositions for the delivery of atherapeutic agent and to related methods, and more particularly relatesto compositions containing one or more alkoxy-polyethylene glycols forthe delivery of a therapeutic agent and to related methods.

BACKGROUND

The administration of a therapeutic agent by injection (e.g.,intravenous, intramuscular or subcutaneous injection) typically isregarded as the most convenient way of administration when the purposeis to achieve a rapid and strong systemic effect, for example, within3-10 minutes, when the agent is not absorbed by the gastrointestinaltract, or when the agent is inactivated in the gastrointestinal tract orby first-pass hepatic metabolism. However, administration by injectionpresents a range of disadvantages. For example, sterile syringes must beused and injections cannot be administered by untrained personnel.Furthermore, this mode of administration may cause pain and/orirritation, especially in the case of repeated injections at the samesite.

Mucosal administration, such as, intranasal, buccal, sublingual, rectaland pulmonal administration, is receiving particular interest as itavoids many of the disadvantages of injecting a therapeutic agent while,at the same time, still providing a strong and rapid systemic effect. Inorder to be an attractive alternative to injection, mucosaladministration, for example, intranasal administration, should neithercause significant pain, discomfort or irritation nor cause anyirreversible damage to the mucosal surface. However, in the case ofacute health threatening indications, a relatively high local irritationto the mucosa may be acceptable.

In mucosal administration, such as during nasal, buccal or rectaladministration, the therapeutic agent should be applied to the mucosa ina vehicle that permits it to penetrate, or be absorbed through, themucosa. In order to penetrate the mucus, the vehicle should bebiocompatible with mucus and hence have a certain degree ofhydrophilicity. However, the vehicle should preferably also possesslipophilic properties to dissolve a clinically relevant amount of thetherapeutic agent of interest.

The extensive network of blood capillaries under the mucosal surface,especially in the nasal mucosa, is well suited to provide a rapid andeffective systemic absorption of drugs, vaccines and biologicals.Moreover, the nasal epithelial membrane in effect contains a singlelayer of epithelial cells (pseudostratified epithelium) and, therefore,is more suited for drug administration than other mucosal surfaceshaving squamous epithelial layers, such as, the mouth and vagina.

It has been hypothesized that the usefulness of nasal administration canbe limited if the therapeutic agent has limited solubility in water(Proctor, D. F. (1985) Nasal Physiology in Intranasal DrugAdministrations, in Chien, Y. W. (Ed.) TRANSNASAL SYSTEMIC MEDICATIONS,FUNDAMENTALS, DEVELOPMENTAL CONCEPTS AND BIOMEDICAL ASSESSMENTS,ELSEVIER Science Publishers, Amsterdam, pp. 101-105). As a result, thishypothesis, if correct, may limit the delivery of certain therapeuticagents that are sparingly soluble in water.

To facilitate delivery to the nasal cavity, an effective amount of thetherapeutic agent should be dissolved in a small volume, for example,less than about 1000 μL, preferably less than 300 μL, and morepreferably less than 150 μL. Larger volumes drain out anteriorly throughthe nostrils or posteriorly toward the pharynx where excess liquid isswallowed. As a result, if large volumes are administered, a portion ofthe therapeutic agent can be lost from the absorption site, and it canbe difficult if not impossible to reproducibly administer the correctdose of the therapeutic agent.

A variety of delivery systems have been developed for the nasaladministration of therapeutic agents. Lau and Slattery studied theabsorption characteristics of diazepam and lorazepam following theirintranasal administration for the treatment of epilepticus (Lau, S. W.J. & Slattery, J. T. (1989), Absorption of Diazepam and LorazepamFollowing Intranasal Administration, INT. J. PHARM., 54, 171-174). Inorder to solubilize the therapeutic agent, a non-ionicsurfactant—polyoxyethylated castor oil—was selected as the leastirritating solvent of several solvents studied, including polyethyleneglycol 400 (PEG 400). Diazepam absorption was 84% and 72%, respectively,in two adults measured over a period of 60 hours. However, the peakconcentration was not observed until 1.4 hours after the nasaladministration and was only about 27% with reference to intravenousadministration, suggesting that most of the absorption had taken placeafter the test substance passed down to pharynx and swallowed. Similarresults were obtained for lorazepam but with an even longer time to peak(2.3 hours). The authors concluded that the intranasal route ofadministration had limited potential for the acute treatment ofepileptic seizures.

Wilton et al. attempted to administer midazolam to 45 children toachieve pre-anesthetic sedation (Wilton et al. (1988) PreanaestheticSedation of Preschool Children Using Intranasal Midazolam,ANESTHESIOLOGY, 69, 972-975). However, the volumes used were impracticaland exceeded the maximal volume required for efficient administration.This resulted in coughing and sneezing with expulsion of at least partof the dose.

Morimoto et al. studied a gel preparation for nasal application in ratsof nifedipine containing the gelling agent carbopol (polyacrylic acid)in PEG 400, for achieving prolonged action and high bioavailability ofthe therapeutic agent (Morimoto et al. (1987) Nasal Absorption ofNifedipine from Gel Preparations in Rats, CHEMICAL AND PHARMACEUTICALBULLETINS, 35, No. 7, 3041-3044). A mixture of equal amounts of carbopoland PEG 400 was preferred. It was shown that nasal application providedhigher bioavailability of nifedipine than after peroral administration,but the peak plasma concentration was not observed until 30 minutesafter administration.

Danish Patent Application No. 2586/87 discloses a pharmaceuticalcomposition comprising an anti-inflammatory steroid, water, 2 to 10%(v/v) propylene glycol, 10 to 25% (v/v) PEG 400, and 1 to 4% (v/v) Tween20.

U.S. Pat. No. 4,153,689 discloses a stable aqueous solution of insulinintended for intranasal administration. The solutions had a pH not morethan 4.7, and contained from 0.1 to 20% by weight of a stabilizing agentincluding (a) one or more non-ionic surface active agents whosehydrophile-lipophile balance value was in the range of 9 to 22, and/or(b) polyethylene glycol whose molecular weight was in the range of from200 to 7500. Exemplary non-ionic surface active agents includedpolyoxyethylene fatty acid ester, a polyoxyethylene higher alcoholether, a polyoxyethylene alkylphenyl ether, or a polyoxyethylenealkylphenyl ether, or a polyoxyethylene hydrogenated castor oil.

International Patent Publication No. DK-2075/90 discloses the nasaladministration of therapeutic agents, for example, benzodiazepines, incompositions containing n-glycofurol, a derivative ofpolyethyleneglycol, for mucosal administration. The applicationdiscloses the nasal administration of therapeutic agents, for example,benzodiazepines, in formulations containing at least 30%n-ethyleneglycols ranging from 1-8 ethylene glycol, for example,polyethylene glycol 200 (PEG 200).

U.S. Pat. No. 5,693,608 discloses a method of administering atherapeutic agent via the nasal mucosa of a mammal, where the agent isdissolved or suspended in an n-ethyleneglycol containing vehicle wherethe n-ethyleneglycol is represented by the formula, H(OCH₂CH₂)_(p)OH,wherein p is a number from 1 to 8.

Notwithstanding, there is still a need for compositions deliverablethrough mucosal membranes that produce therapeutic plasma concentrationsof the therapeutic agent as fast as or nearly as fast as by intravenousadministration but without causing irritation and/or unacceptable damageto the mucosal membrane.

SUMMARY OF THE INVENTION

The invention is based, in part, upon the discovery that the inclusionof one or more alkoxy-polyethylene glycols in a formulation providescertain advantages when the resulting composition is to be applied, forexample, to a mucosal surface. For example, it has been discovered thatwhen alkoxy-polyethylene glycol is used in such formulations, thetherapeutic agent can be still be solubilized (which is especiallyuseful for poorly soluble therapeutic agents) but the resultingformulations are less viscous and cause less irritation to mucosalmembranes because the amount of other potentially viscous and irritableexcipients, for example, polyethylene glycol or propylene glucol, can bereduced or eliminated altogether. As a result, the lower viscosityformulations, when converted into droplets, for example, by a nasalsprayer during intranasal delivery, can produce a spray patternoptimized for delivering the therapeutic agent to the mucosal membrane.In addition, formulations containing alkoxy-polyethylene glycols createless irritation (burning sensation) when applied to a mucosal surface,for example, a nasal membrane following nasal administration. Inaddition, when administered intranasally, the compositions of theinvention minimize undesirable after taste (for example, apetroleum-like after taste) that can be associated with certain otherexcipients.

In one aspect, the invention provides a liquid pharmaceuticalcomposition comprising a therapeutic agent and an alkoxy-polyethyleneglycol represented by Formula I:

R—O—(CH₂CH₂O)_(n)—H  (I)

wherein,

R is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; and

n, which is the average number of oxyethylene repeating units, is anumber in the range of from about 1 to about 25.

In another aspect, the invention provides a liquid formulation forsolubilizing a poorly soluble therapeutic agent, for example, a poorlysoluble organic therapeutic agent. The composition comprises a poorlysoluble therapeutic agent and an alkoxy-polyethylene glycol representedby Formula I:

R—O—(CH₂CH₂O)_(n)—H  (I)

wherein,

R is (C₁-C₆)alkyl; and

n, which is the average number of oxyethylene repeating units, is anumber in the range of from about 1 to about 25.

In another aspect, the invention provides methods of delivering atherapeutic agent of interest to a mammal, for example, a human, usingan alkoxy-polyethylene glycol containing composition described herein.The composition is particularly useful when the composition is appliedto a mucosal membrane, for example, a nasal membrane during intranasaldrug delivery.

These and other aspects and advantages of the invention will becomeapparent upon consideration of the following detailed description andclaims.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based, in part, upon the discovery that the inclusionof one or more alkoxy-polyethylene glycols into formulations providescertain advantages over other excipients when the formulations areapplied, for example, to a mucosal surface. For example, it has beendiscovered that when an alkoxy-polyethylene glycol is used in such aformulation, the therapeutic agent (for example, a poorly solubletherapeutic agent) can be solubilized more easily and in larger amountsthan when other excipients, for example, polyethylene glycol (moreparticularly PEG 400), are used. However, the resulting formulations areless viscous and cause less irritation to mucosal membranes as theamount of other viscous and irritable excipients can be reduced oreliminated altogether. As a result, the lower viscosity formulations,when converted into droplets, for example, by a nasal sprayer duringintranasal delivery, produce a spray pattern optimized for deliveringthe therapeutic agent to the mucosal membrane. In addition, formulationscontaining one or more alkoxy-polyethylene glycols cause less irritation(for example, a burning sensation) when applied to a mucosal surface,for example, a nasal membrane during intranasal administration. Inaddition, when administered intranasally, the compositions of theinvention have less undesirable after taste (for example, apetroleum-like after taste) than when other excipients, for example,propylene glycol, are used.

Under certain circumstances, the alkoxy-group also increases thebioadhesion of the composition to the site of administration on themucosal surface thereby prolonging the duration of the composition atthe site of administration. This can increase the amount of therapeuticagent that is ultimately absorbed.

I Formulations

In one aspect, the invention provides a liquid pharmaceuticalcomposition comprising a therapeutic agent and an alkoxy-polyethyleneglycol represented by Formula I:

R—O—(CH₂CH₂O)_(n)—H  (I)

wherein,

R is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl; and

n is the average number of oxyethylene repeating units and is a numberin the range of from about 1 to about 25.

In another aspect, the invention provides a liquid formulation forsolubilizing a poorly soluble therapeutic agent. The liquidpharmaceutical composition comprises a poorly soluble therapeutic agent,for example, a poorly soluble organic therapeutic agent, and analkoxy-polyethylene glycol represented by Formula I:

R—O—(CH₂CH₂O)_(n)—H  (I)

wherein,

R is (C₁-C₆)alkyl; and

n is the average number of oxyethylene repeating units and is a numberin the range of from about 1 to about 25. The formulations typically arein liquid form at 20° C., 25° C., 30° C., 35° C., or 40° C. Certainformulations preferably are liquid formulations at 37° C.

The term “poorly soluble therapeutic agent” refers to a compound havingbiological activity and a solubility in water of less than about 1 mg/mLat pH 7 and 20° C. In certain embodiments, the poorly solubletherapeutic agent is an organic compound that has a molecular weight ofless than 1500 g/mol, and preferably less than 500 g/mol. In certainembodiments, the poorly soluble therapeutic agent is a compound, forexample, an organic compound, having an aqueous solubility of less thanabout 0.5 mg/mL, less than about 0.3 mg/mL, or less than about 0.1mg/mL, at pH 7 and 20° C.

In addition, the term “alkyl” is art-recognized, and includes saturatedaliphatic groups, including straight-chain alkyl groups, branched-chainalkyl groups, cycloalkyl (alicyclic) groups, alkyl substitutedcycloalkyl groups, and cycloalkyl substituted alkyl groups. The term“(C₁-C₆)alkyl” refers to an alkyl group having between 1 and 6 carbonatoms. Representative alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl,cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclopentyl,cyclobutylmethylene, cyclobutylethylene, cyclohexyl,cyclopropylpropylene, cyclobutylethylene, and cyclopentylmethylene. Theterm cyclopropylmethylene, for example, is art-recognized and refers toa radical having the following formula:

In certain embodiments, the alkoxy-polyethylene glycol can comprise fromabout 0.1% (v/v) to about 80% (v/v), or from about 0.5% (v/v) to about70% (v/v), of the composition. In certain other embodiments, thealkoxy-polyethylene glycol can comprise from about 5% (v/v) to about 80%(v/v), or from about 30% (v/v) to about 75% (v/v) or from about 40%(v/v) to about 70% (v/v), of the composition. For certain hydrophilicdrugs, the alkoxy-polyethylene glycol can comprise from about 0.1% (v/v)to about 80% (v/v), or from about 0.5% (v/v) to about 70% (v/v), or fromabout 1% (v/v) to about 60% of the composition. For certain lipophilicdrugs, the alkoxy-polyethylene glycol can comprise from about 1% (v/v)to about 80% (v/v), or from about 2% (v/v) to about 65% (v/v), or fromabout 5% (v/v) to about 50% of the composition. Furthermore, thetherapeutic agent can comprise from about 0.001% (w/v) to about 20%(w/v) of the composition, or from about 0.1% (w/v) to about 10% (w/v) ofthe composition.

The pharmaceutical composition can have a pH in the range of from about4.5 to about 8.5, or from about 4.5 to about 7.5, or from about 4.5 toabout 6.5, or from about 5.5 to about 8.5, or from about 6.5 to about8.5, or from about 5.5 to about 7.5.

As discussed, one of the advantages of using an alkoxy-polyethyleneglycol is that it can be used in place of or can be used to reduce theamount of other excipients, for example, certain polyethylene glycolsand propylrnr glycol, so as to reduce the viscosity of the resultingformulation. By reducing the viscosity of the resulting formation it ispossible to create sprays that have more uniform spray characteristics(for example, more uniform droplet sizes and/or plume geometries) forthe intranasal administration of therapeutic agent. The resultingpharmaceutical composition at a temperature of 20° C. has a viscosity inthe range of about 1.5 cP to about 60 cP, or from about 2 cP to about 50cP, or from about 3 cP to about 40 cP, or from about 4 cP to about 30cP, or from about 5 cP to about 25 cP.

Exemplary alkoxy-polyethylene glycols, therapeutic agents, and otherexcipients useful in creating compositions of the invention aredescribed in the following sections.

A. Alkoxy-polyethylene Glycol

Useful alkoxy-polyethylene glycol excipients useful in the practice ofthe invention are represented by Formula (I):

R—O—(CH₂CH₂O)_(n)—H  (I)

wherein, n, as the average number of oxyethylene repeating units, is anumber in the range of from about 1 to about 25. Accordingly, n can be anumber about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, or 25. In certain embodiments, n is annumber in the range of from about 2 to about 15, or from about 2 toabout 14, or from about 2 to about 13, or from about 2 to about 12, orfrom about 2 to about 11, or from about 2 to about 10, or from about 3to about 15, or from about 3 to about 14, or from about 3 to about 13,or from about 3 to about 12, or from about 3 to about 11, or from about3 to about 10.

In certain embodiments, R is (C₁-C₆)alkyl. For example, as discussedabove, R can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl,cyclopropylmethylene, cyclopentyl, cyclobutylmethylene,cyclobutylethylene, cyclohexyl, cyclopropylpropylene,cyclobutylethylene, or cyclopentylmethylene. In certain embodiments, Ris selected from the group consisting of methyl, ethyl, n-propyl,isopropyl, and cyclopropyl.

In a preferred embodiment, the alkoxy-polyethylene glycol ismethoxy-polyethylene glycol where R is methyl and n is an number fromabout 1 to about 25, or from about 2 to about 12, or from about 3 toabout 10.

Useful methoxy-polyethylene glycols include, for example,methoxy-diethyleneglyol (m2EG), methoxy-triethylene glycol (m3EG),methoxy-tetraethylene glycol (m4EG), methoxy-pentaethylene glycol(m5EG), methoxy-hexaethylene glycol (m6EG), methoxy-heptaethylene glycol(m7EG), methoxy-octaethylene glycol (m8EG), methoxy-nonaethylene glycol(m9EG), methoxy-decaethylene glycol (m10EG), methoxy-undecaethyleneglycol (m11EG), methoxy-dodecaethylene glycol (m12EG),methoxy-tridecaethylene glycol (m13EG) and methoxy-tetradecaethyleneglycol (m14EG). The ethylene glycols may be used in the form of thesingle compounds or as a mixture of two or more methoxy-n-ethyleneglycols.

In certain embodiments, the alkoxy-polyethylene glycol ismethoxy-polyethylene glycol 350 (mPEG 350) or is methoxy-polyethyleneglycol 550 (mPEG 550) or is methoxy-polyethylene glycol 750 (mPEG 750).The term “mPEG 350” is understood to mean methoxy polyethylene glycolhaving an average molecular weight of about 350, and in certainembodiments “n,” as denoted in Formula I, is 7.2. The term “mPEG550” isunderstood to mean methoxy polyethylene glycol having an averagemolecular weight of about 550, and in certain embodiments “n,” asdenoted in Formula I, is 11.8. The term “mPEG750” is understood to meanmethoxy polyethylene glycol having an average molecular weight of about750, and in certain embodiments “n,” as denoted in Formula I, is 16.3.

Certain, preferred alkoxy-polyethylene glycols include Carbowax™ mPEG350, Carbowax™ mPEG 550 or Carbowax™ mPEG 750, which are availablecommercially from Dow Chemical Company. Both mPEG350 and mPEG550 arecolorless liquids that are miscible with water, alcohols, such asmethanol, ethanol, n-propanol, glycerol and various oils in allproportions, and have a boiling point about 155° C. It is understoodthat alkoxy-polyethylene glycols are known by other names, where, forexample, methoxy-polyethylene glycol is also known as mono-methylpolyethylene glycol and poly(ethylene glycol) methyl ether.

By using one or more of the alkoxy-polyethylene glycols describedherein, the resulting pharmaceutical compositions can be optimized, forexample, with respect to bioadhesion, viscosity and sprayability. Forexample, mPEG 350, at an equivalent concentration as PEG 200, can stillsolubilize a therapeutic agent but the resulting composition has a lowerviscosity. As a result, this substitution has a surprisingly positiveeffect on the sprayability compared with lower molecular weight PEG 200,which is important where the formulation is to be sprayed.

B. Therapeutic Agent

The pharmaceutical composition of the invention may comprise one or moretherapeutic agents (also referred to as biologically active substances)selected from the group consisting of hydrophobic therapeutic agents,hydrophilic therapeutic agents, and combinations thereof.

The alkoxy-polyethylene glycol excipients are surprisingly capable ofsolubilizing and delivering a wide variety of hydrophilic andhydrophobic therapeutic agents. The hydrophobic drugs have little or nowater solubility. It is understood that the excipients described hereincan be used to solubilize therapeutic agents that have a solubility inwater of less than about 1.0 mg/mL, less than about 0.5 mg/mL, less thanabout 0.3 mg/mL, or less than about 0.1 mg/mL, or less than about 0.01mg/mL, at pH 7 and 20° C. Such therapeutic agents can be any agentshaving therapeutic or other value when administered to a mammal, forexample, a human, and can include organic molecules (for example, smallmolecule drugs having a molecular weight of less than 1,500 g/mol., orless than 500 g/mol.), proteins, peptides, immungens (e.g. vaccines,cytokines, etc.), nutrients, and cosmetics (cosmeceuticals).

In certain embodiments, the therapeutic agent is an analgesic agent, ananti-inflammatory agent, an anti-arrhythmic agent, an anti-asthma agent,an anti-bacterial agent, an anti-viral agent, an anti-coagulant, ananti-depressant, an anti-diabetic, an anti-epileptic, an anti-fungalagent, an anti-hypertensive agent, an anti-malarial, an anti-migraineagent, an anti-muscarinic agent, an anti-neoplastic agent, animmunosuppressant, an anti-protozoal agent, an anti-thyroid agent, ananxiolytic agent, a sedative, a hypnotic agent, a neuroleptic agent, abeta-Blocker, a cardiac inotropic agent, a corticosteroid, a diureticagent, an anti-Parkinsonian agent, a gastrointestinal agent, ananti-histamine, a histamine-receptor antagonist, a lipid regulatingagent, a muscle relaxant, nitrate and other anti-anginal agent, anutritional agent, an opioid analgesic, sex hormone, stimulant,cytokine, peptidomimetic, peptide, protein, toxoid, sera, antibody,vaccine, nucleoside, nucleotide, nucleic acid and peptidyl-nucleic acid.

Specific non-limiting examples of hydrophobic therapeutic agents thatcan be used in the pharmaceutical compositions of the present inventioninclude the following representative compounds, as well as theirpharmaceutically acceptable salts, isomers, esters, ethers and otherderivatives including, for example: (1) analgesics and anti-inflammatoryagents, such as, aloxiprin, auranofin, azapropazone, benorylate,capsaicin, celecoxib, diclofenac, diflunisal, etodolac, fenbufen,fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, leflunomide, meclofenamic acid, mefenamic acid, nabumetone,naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam,refocoxib, sulindac, tetrahydrocannabinol, tramadol and tromethamine;(2) anti-arrhythmic agents, such as, amiodarone HCl, disopyramide,flecainide acetate and quinidine sulfate; (3) anti-asthma agents, suchas, zileuton, zafirlukast, montelukast, and albuterol; (4)anti-bacterial agents, such as, baclofen, benzathine penicillin,cinoxacin, clarithromycin, clofazimine, cloxacillin, demeclocycline,dirithromycin, doxycycline, erythromycin, ethionamide, furazolidone,grepafloxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl,nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin,rifabutine, rifapentine, sparfloxacin, spiramycin, sulphabenzamide,sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine,sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline,trimethoprim and trovafloxacin; (5) anti-viral agents, such as,abacavir, amprenavir, delavirdine, efavirenz, indinavir, lamivudine,nelfinavir, nevirapine, ritonavir, saquinavir, and stavudine; (6)anti-coagulants, such as, cilostazol, clopidogrel, dicumarol,dipyridamole, nicoumalone, oprelvekin, phenindione, ticlopidine, andtirofiban; (7) anti-depressants, such as amoxapine, bupropion,citalopram, clomipramine, maprotiline HCl, mianserin HCl, nortriptylineHCl, paroxetine HCl, sertraline HCl, trazodone HCl, trimipraminemaleate, and venlafaxine HCl; (8) anti-diabetics, such as,acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide,glimepiride, miglitol, pioglitazone, repaglinide, rosiglitazone,tolazamide, tolbutamide and troglitazone; (9) anti-epileptics, such as,beclamide, carbamazepine, clonazepam, ethotoin, felbamate, fosphenytoinsodium, lamotrigine, methoin, methsuximide, methylphenobarbitone,oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenyloin,phensuximide, primidone, sulthiame, tiagabine HCl, topiramate, valproicacid, and vigabatrin; (10) anti-fungal agents, such as, amphotericin,butenafine HCl, butoconazole nitrate, clotrimazole, econazole nitrate,fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole,miconazole, natamycin, nystatin, sulconazole nitrate, oxiconazole,terbinafine HCl, terconazole, tioconazole and undecenoic acid; (11)anti-hypertensive agents, such as, amlodipine, benidipine, benezepril,candesartan, captopril, darodipine, dilitazem HCl, diazoxide, doxazosinHCl, elanapril, eposartan, losartan mesylate, felodipine, fenoldopam,fosenopril, guanabenz acetate, irbesartan, isradipine, lisinopril,minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine,phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin HCl,telmisartan, and valsartan; (12) anti-malarials, such as, amodiaquine,chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl,proguanil HCl, pyrimethamine and quinine sulfate; (13) anti-migraineagents, such as, dihydroergotamine mesylate, ergotamine tartrate,frovatriptan, methysergide maleate, naratriptan HCl, pizotyline malate,rizatriptan benzoate, sumatriptan succinate, and zolmitriptan; (14)anti-muscarinic agents, such as, atropine, benzhexol HCl, biperiden,ethopropazine HCl, hyoscyamine, oxyphencyclimine HCl and tropicamide;(15) anti-neoplastic agents and immunosuppressants, such as,aminoglutethimide, amsacrine, azathioprine, bicalutamide, bisantrene,busulfan, camptothecin, chlorambucil, cyclosporin, dacarbazine,ellipticine, estramustine, etoposide, irinotecan, lomustine, melphalan,mercaptopurine, mitomycin, mitotane, mitoxantrone, mofetilmycophenolate, nilutamide, paclitaxel, procarbazine HCl, sirolimus,tacrolimus, tamoxifen citrate, teniposide, testolactone, topotecan HCl,and toremifene citrate; (16) anti-protozoal agents, such as, atovaquone,benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline,diloxanide furoate, dinitolmide, furazolidone, metronidazole,nimorazole, nitrofurazone, ornidazole and tinidazole; (17) anti-thyroidagents, such as, carbimazole, paracalcitol, and propylthiouracil;anti-tussives, such as, benzonatate; (18) anxiolytics, sedatives,hypnotics and neuroleptics, such as, alprazolam, amylobarbitone,barbitone, bentazepam, bromazepam, bromperidol, brotizolam,butobarbitone, carbromal, chlordiazepoxide, chlormethiazole,chlorpromazine, chlorprothixene, clonazepam, clobazam, clotiazepam,clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,triflupromazine, fluphenthixol decanoate, fluphenazine decanoate,flurazepam, gabapentin, haloperidol, lorazepam, lormetazepam, medazepam,meprobamate, mesoridazine, methaqualone, methylphenidate, midazolam,molindone, nitrazepam, olanzapine, oxazepam, pentobarbitone,perphenazine pimozide, prochlorperazine, pseudoephedrine, quetiapine,rispiridone, sertindole, sulpiride, temazepam, thioridazine, triazolam,zolpidem, and zopiclone; (19) beta-Blockers, such as, acebutolol,alprenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol andpropranolol; (20) cardiac inotropic agents, such as, amrinone,digitoxin, digoxin, enoximone, lanatoside C and medigoxin; (21) acorticosteroid, such as, beclomethasone, betamethasone, budesonide,cortisone acetate, desoxymethasone, dexamethasone, fludrocortisoneacetate, flunisolide, fluocortolone, fluticasone propionate,hydrocortisone, methylprednisolone, prednisolone, prednisone andtriamcinolone; (22) diuretics, such as, acetazolamide, amiloride,bendroflumethiazide, bumetanide, chlorothiazide, chlorthalidone,ethacrynic acid, frusemide, metolazone, spironolactone and triamterene;(23) anti-Parkinsonian agents, such as, bromocriptine mesylate, lysuridemaleate, pramipexole, ropinirole HCl, and tolcapone; (24)gastrointestinal agents, such as bisacodyl, cimetidine, cisapride,diphenoxylate HCl, domperidone, famotidine, lansoprazole, loperamide,mesalazine, nizatidine, omeprazole, ondansetron HCl, rabeprazole sodium,ranitidine HCl and sulphasalazine; (25) anti-histamines andhistamine-receptor antagonists, such as, acrivastine, astemizole,chlorpheniramine, cinnarizine, cetrizine, clemastine fumarate,cyclizine, cyproheptadine HCl, dexchlorpheniramine, dimenhydrinate,fexofenadine, flunarizine HCl, loratadine, meclizine HCl, oxatomide, andterfenadine; (26) lipid regulating agents, such as, atorvastatin,bezafibrate, cerivastatin, ciprofibrate, clofibrate, fenofibrate,fluvastatin, gemfibrozil, pravastatin, probucol, and simvastatin; (27)muscle relaxants, such as, dantrolene sodium and tizanidine HCl; (28)nitrates and other anti-anginal agents, such as, amyl nitrate, glyceryltrinitrate, isosorbide dinitrate, isosorbide mononitrate andpentaerythritol tetranitrate; (29) nutritional agents, such as,calcitriol, carotenes, dihydrotachysterol, essential fatty acids,non-essential fatty acids, phytonadiol, vitamin A, vitamin B₂, vitaminD, vitamin E and vitamin K; (30) opioid analgesics, such as, codeine,dextropropoxyphene, diamorphine, dihydrocodeine, fentanyl, meptazinol,methadone, morphine, hydromorphone, nalbuphine and pentazocine; (31) sexhormones, such as, clomiphene citrate, cortisone acetate, danazol,dehydroepiandrosterone, ethynyl estradiol, finasteride, fludrocortisone,fluoxymesterone, medroxyprogesterone acetate, megestrol acetate,mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol,conjugated estrogens, progesterone, rimexolone, stanozolol, stilbestrol,testosterone and tibolone; and (32) stimulants, such as, amphetamine,dexamphetamine, dexfenfluramine, fenfluramine and mazindol; and others,such as, becaplermin, donepezil HCl, L-thryroxine, methoxsalen,verteporfrin, physostigmine, pyridostigmine, raloxifene HCl, sibutramineHCl, sildenafil citrate, tacrine, tamsulosin HCl, and tolterodine.

Certain exemplary hydrophobic therapeutic agents include sildenafilcitrate, amlodipine, tramadol, celecoxib, rofecoxib, oxaprozin,nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast,cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine,loratadine, famotidine, paricalcitol, atovaquone, nabumetone,alprazolam, bromazepam, chlorpromazine, clonazepam, diazepam,flunitrazepam, flurazepam, haloperidol, lorazepam, lormetazepam,midazolam, nitrazepam, oxazepam, pseudoephedrine, temazepam, triazolam,zolpidem, zopiclone, tetrahydrocannabinol, testosterone, megestrolacetate, repaglinide, progesterone, rimexolone, cyclosporin, tacrolimus,sirolimus, teniposide, paclitaxel, pseudoephedrine, troglitazone,rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, andpharmaceutically acceptable salts, isomers and derivatives thereof. Itshould be appreciated that the listing of hydrophobic therapeutic agentsand their therapeutic classes is merely illustrative. It is understood,that mixtures of hydrophobic therapeutic agents may also be used wheredesired.

An advantage of using alkoxy-polyethylene glycol as an excipient in thepharmaceutical composition is that, for example, highly lipophilicsubstances, such as, lorazepam, midazolam, clonazepam, alprazolam andother compounds belonging to the benzodiazepines, as well as watersoluble substances, for example, peptides and proteins, such as, thepancreatic hormones can be solubilized in a clinically relevant volume(for example, 25-300 μL) for delivery to a human subject. By way ofcomparison, clinically relevant doses of midazolam, lorazepam,alprazolam, diazepam and clonazepam would have to be dissolved in atleast 5 mL of water.

Although the alkoxy-polyethylene glycol excipients are particularlyuseful for the delivery of hydrophobic agents, alkoxy-polyethyleneglycol can also be used to deliver a variety of hydrophilic therapeuticagents. Alkoxy-polyethylene glycols, under certain circumstances, mayprolong the duration of the therapeutic agent at the absorption sitethereby increasing the amount of agent ultimately delivered. Exemplaryhydrophilic therapeutic agents include hydrophilic drugs (i.e.,conventional non-peptidic drugs), hydrophilic macromolecules, such as,cytokines, peptides, proteins, peptidomimetics, toxoids, sera,antibodies, vaccines, nucleosides, nucleotides, nucleic acids, andgenetic material. The hydrophilic therapeutic agent can be administeredalone or in combination with other agents, for example, a hydrophobictherapeutic agent discussed hereinabove or a second, differenthydrophilic therapeutic agent.

Without limitation, exemplary hydrophilic therapeutic agents that can bedelivered using the compositions and methods of the present invention,include the following compounds as well as their pharmaceuticallyacceptable salts, isomers, esters, ethers and other derivatives, forexample: acarbose; acyclovir; acetyl cysteine; acetylcholine chloride;alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride;ambenomium; amifostine; aminocaproic acid; antihemophilic factor(human); antihemophilic factor (porcine); antihemophilic factor(recombinant); aprotinin; asparaginase; atenolol; atracurium besylate;azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona;bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitoninsalmon; carboplatin; capecitabine; capreomycin sulfate; cefamandolenafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicidsodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium;ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirinsodium; cholera vaccine; chorionic gonadotropin; cidofovir; cisplatin;cladribine; clidinium bromide; clindamycin and clindamycin derivatives;ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate;cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperinsodium; danaproid; deforoxamine; denileukin diftitox; desmopressin;diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine;dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin;editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprinsodium; ephedrine; epinephrine; epoetin alpha; esmol hydrochloride;Factor IX; famiciclovir; fludarabine; fluoxetine; foscarnet sodium;ganciclovir; granulocyte colony stimulating factor;granulocyte-macrophage stimulating factor; growth hormones (human orbovine); gentamycin; glucagon; glycopyrolate; gonadotropin releasinghormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin;hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated;Hepatitis B virus vaccine inactivated; heparin sodium; indinavirsulfate; influenza virus vaccine; interleukin-2; interleukin-3;insulin-human; insulin-porcine; insulin NPH; insulin aspart; insulinglargine; insulin detemir; interferon-α; interferon-β; ipratropiumbromide; isofosfamide; japanese encephalitis virus vaccine; leucovorincalcium; leuprolide acetate; levofloxacin; lincomycin and lincomycinderivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measlesvirus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide;mesalmine; methanamine; methotrexate; methscopolamine; metforminhydrochloride; metroprolol; mezocillin sodium; mivacurium chloride;mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigminemethyl sulfate; neutontin; norfloxacin; octreotide acetate; olpadronate;oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline;periciclovir; pentagastrin; phentolamine mesylate; phenylalanine;physostigmine salicylate; plague vaccine; piperacillin sodium; plateletderived growth factor-human; pneumococcal vaccine polyvalent; poliovirusvaccine (live or inactivated); polymixin B sulfate; pralidoxinechloride; pramlintide; pregabalin; propofenone; propenthaline bromide;pyridostigmine bromide; rabies vaccine; residronate; ribavarin;rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate;sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin;spectinomycin; stavudine; streptokinase; streptozocin; suxamethoniumchloride; tacrine hydrochloride; terbutaline sulfate; thiopeta;ticarcillin; tiludronate; timolol; tissue type plasminogen activator;TNFR:Fc; TNK-tPA; trandolapril; trimetrexate gluconate;trospectinomycin; trovafloxacin; tubocurarine chloride; tumor necrosisfactor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir;varicella virus vaccine live; vasopressin and vasopessin derivatives;vecoronium bromide; vinbiastin; vincristine; vinorelbine;warfarin-sodium; yellow fever vaccine; zalcitabine; zanamavir;zolandtronate; and zidovudine.

Other therapeutic agents that can be administered in this formulationmay comprise adrenal hormones, corticosteroids and derivatives, such as,ACTH and analogs thereof, teracosactrin, alsactide, cortisone,hydrocortisone alcohol, hydrocortisone acetate, hydrocortisonehemisuccinate, prednisolone terbutate, 9-alpha-fluoroprednisolone,triamcinolone acetonide, dexamethasone phosphate, flurisolide, toxicorolpivalate; anorectics, such as, benzphetamine HCl chlorphentermine HCl;antibiotics, such as, tetracycline HCl, tyrothricin, cephalosporine,aminoglycosides, streptomycin, gentamycin, leucomycin, penicillin andderivatives; anti-allergic agents; antibodies, such as, monoclonal orpolyclonal antibodies; anti-cholinergic agents; anti-depressants, suchas, amitriptyline HCl, imipramine HCl; anti-emitics, such as,neuroleptica, for example, metopimazin, anti-emetics having a regulatoryeffect on the motility of the intestine, such as, domperidon;anti-histaminic agents and histaminic agents, such as, diphenhydraminHCl, chloropheniramine maleate, histamine, prophenpyridamine maleate,chlorprophenpyridamine maleate, disodium cromoglycate, meclizine;anti-hypertensive agents, such as, clonidine HCl; anti-inflammatoryagents (enzymatic), such as, chymotrypsin, bromelain seratiopeptidase;anti-inflammatory agents (non-steroidal), such as, acetaminophen,aspirin, aminopyrine, phenylbutazone, colchicine, probenocid;anti-inflammatory agents (steroidal), such as, fluticasone,predonisolone, triaxncinolone acetonide; anti-neoplastic agents, suchas, actinomycin C.; anti-septics, such as, chlorhexidine HCl,hexylresorcinol, dequalinium cloride, ethacridine; anti-tussiveexpectorant (asthmatic agents), such as, sodium cromoglycate,isoprotereol HCl; anti-viral and anti-cancer agents such as interferons(such as alpha-2 interferon for treatment of common colds),phenyl-p-guanidino benzoate, enviroxime, etc.; beta-adrenergic blockingagents, such as, propranolol HCl; blood factors, such as, factor VII,factor VIII; bone metabolism controlling agents, such as, vitamin D₃;bronchoisters, such as, clenbuterol HCl, bitolterol mesylate;cardiotonics such as digitalis; cardiovascular regulatory hormones,drugs and derivatives, such as, bradykin antagonists, atrial natriureticpeptide and derivatives, such as, hydrailsazine, angiotensin IIantagonist, nitroglycerin, propranolol, clofilium rosylate;chemotherapeutic agents, such as, sulphathiazole, nitrofurazone;CNS-stimulants, such as, lidocaine, cocaine; corticosteroids, such as,lacicortone, hydrocorticeone, fluocinolone acetonide, triamcinoloneacetonide; enzymes, such as, lysozyme chloride, dextranase;gastrointenstinal hormones and derivatives, such as, secretin, substanceP; hypothalamus hormones and derivatives, such as, LHRH and analogues(such as naferelin, buserelin, zolidex), TRH (thyrotropin releasinghormone); hypothensives; local anaesthetics, such as, benzocaine;migraine treatment substances, such as, dihydroergot amine, ergometrine,ergotamine, pizotizin; pancreatic hormones and derivatives, such as,insulin (hexameric/dimeric/monomeric forms); parasympathomimetics, suchas, nicotine, methacholine; parasympatholytics, such as, scopolamine,attopine, ipratropium; Parkinson's disease substances, such as,apomorphin; pituitary gland hormones and derivatives, such as, growthhormone (e.g. human), vasopressin and analogues (DDAVP, Lypressin);prostaglandins, such as, PGA and derivatives thereof, PGE₁ andderivatives thereof, PGE₂ and derivatives thereof, PGF₁ and derivativesthereof, dinoprost trometamol; protease inhibitors, such as, citrate, orα₁-antitrypsin; sex-hormones, such as, ethinyloestradiol,levonorgestrel, FSH, LH, LTH, estradiol-17-beta, norethindrone;sympathomimetics, such as, phenylephrine, xylometazoline, tramazoline,dopamine, dobutamine; sleep-aids, such as granistron and ramelteon,tranquilizers, such as, brotizolam, camazepam, chlorazepic acid,cloxazolam, delorazepam, estazolam, ethyl loflazepate, fludiazepam,flutazolam, halazepam, haloxazolam, ketazolam, loprazolam, lormetazepam,nimetazepam, nitrazepam, nordiazepam, oxazepam, pinazepam, prazepam,temazepam, tetrazepam, tofisopam; vaccines, such as, AIDS-vaccines,parainfluenza virus, polio, rhinovirus type 13, respiratory syncytialvirus; vasoconstrictors, such as, phenylephrine HCl, tetrahydrozolineHCl, naphazoline nitrate, oxymetazoline HCl, tramazoline HCl;vasodilators, such as, papaverine HCl, Substance P, vasoactiveintestinal peptide (VIP).

Certain exemplary formulations comprising alkoxy-polyethylene glycolalso comprise one or more therapeutic agents selected from the groupconsisting of peptide drugs, such as, oxytocin, vasopression(desmopresin), insulin, calcitonin, elcatonin, cyanocobalmin B₁₂, andglucagon-like protein-1 (GLP-1), and small organic molecules, such as,dinoprsoone, misoprostol, apomorphine, fentanyl, metoclopramide,butorphanol, and midazolam

C. Other Excipients

It is understood that the compositions of the invention, in addition tothe alkoxy-polyethylene glycol and the therapeutic agent, can comprise anumber of other excipients known to those skilled in the art, includingabsorption promoters, buffering agents, water absorbing polymers,alcohols, lipids, osmotic pressure controlling agents, pH-controllingagents, preservatives, propellants, surfactants, enzyme inhibitors,excipients for adjusting hydrophilic-lipophilic balance (HLB) andstabilizers.

Exemplary surfactants, include, for example nonoxynol, octoxynol,tweens, spans, sodium lauryl sulfate, and sorbitan monopalmitate.Exemplary absorption promoters include, for example, bile salts andderivatives thereof, fusidic acid and derivatives thereof, oleic acid,lecithin, lysolechitins, dodecanoyl phosphatidylcholine (DDPC), sucrosemonododecanoate, n-dodecyl-β-D-maltopyranoside, pectin, chitosan, α-, β-and γ-cyclodextrins and derivatives thereof, pegylated caprylic-/capricglycerides and derivatives thereof, such as, Softigen and Labrasol.Exemplary water absorbing polymers include, for example, polyethyleneglycols having an average molecular weight ranging from 200 to 7500,propylene glycol, or mixtures thereof, or single ethylene glycols suchas tetraethylene glycol and pentaethylene glycol. Exemplary alcoholsinclude, for example, ethanol, isopropyl alcohol. Exemplary lipidsinclude, for example, vegetable oil, soyabean oil, peanut oil, coconutoil, maize oil, olive oil, sunflower oil, monoglycerides, diglycerides,mono/diglycerides, mono/di/triglycerides. Exemplary osmotic pressurecontrolling agents include, for example, glycerol, dextrose, maltose,sucrose, mannitol, xylitol, various salts (for example, sodiumchloride). Exemplary pH-controlling agents include, for example,buffers, acids (for example, nitric acid, phosphoric acid, or aceticacid). Exemplary preservatives include, for example, methylparaoxybenzoate, phenyl ethyl alcohol or benzoic acid. Exemplarypropellants, include, for example, butane or air displacement such asnitrogen. Excipients adjusting the HLB of the formulation include, forexample, Tween 20, 25, 40, 45, 65, 85, Span 20-80, Brij 30-98, acacia.Exemplary enzyme inhibitors include, for example aprotinin and otherpeptidase inhibitors, diisopropylfluorophosphate (DFP), carbopol.Exemplary stabilizers include, for example, cyclodextrins.

Although it is understood that the alkoxy-polyethylene glycols describedherein, for example, methoxy-polyethylene glycol, can solubilize poorlysoluble therapeutic agents, under certain circumstances, it may behelpful to include additional compounds that enhance the solubility ofthe therapeutic agent. Examples of such solubilizers include, forexample, alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, pegylated-mono/di-caprylic/capric glycerides, polyvinylalcohol,hydroxypropyl methylcellulose and other cellulose derivatives,cyclodextrins (for example, α-, β, or γ-cyclodextrins) and cyclodextrinderivatives; ethers of polyethylene glycols having an average molecularweight of about 200 to about 6000 or tetrahydrofurfuryl alcohol PEGether (glycofurol, available commercially from BASF under the trade nameTetraglycol); surfactants, such as, sodium lauryl sulfate, oleic acid,linoleic acid, monoolein, lecithin, lysolecithin, deoxycholate,taurodeoxycholate, glycochenodeoxycholate, polyoxyethylene X-laurylether, where X is from 9 to 20, sodium tauro-24, 25-dihydrofusidate,polyoxyethylene ether, polyoxyethylene sorbitan esters,p-t-octylphenoxypolyoxyethylene, N-lauryl-β-D-maltopyranoside,1-dodecylazacycloheptane-2-azone; amides, such as, 2-pyrrolidone,2-piperidone, caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, and polyvinylpyrrolidone; esters, such as, ethylpropionate, tributylcitrate, acetyl triethylcitrate, acetyl tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate,triacetin, propylene glycol monoacetate, propylene glycol diacetate,caprolactone and isomers thereof, valerolactone and isomers thereof,β-butyrolactone and isomers thereof; and other solubilizers known in theart, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI(ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, anddiethylene glycol monoethyl ether (available from Gattefosse under thetrade name Transcutol).

Preferred additional solubilizers include triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethyleneglycol 200-1000, PEG 300, PEG 400, Transcutol, and dimethyl isosorbide,sorbitol, glycerol, triacetin, glycofurol and propylene glycol.Typically, the solubilizer, if present, is present in an amount of fromabout 0.1% (w/v) to about 50% (w/v), from about 1% (w/v) to about 40%(w/v) or from about 2% (w/v) to about 25% (w/v). In addition, the liquidpharmaceutical composition can comprise water, for example, from about2% (v/v) to about 99% (v/v), from about 10% (v/v) to about 95% (v/v), orfrom about 20% (v/v) to about 90% (v/v), of the liquid composition.

As discussed, the composition can comprise a preservative. In additionor in the alternative, the composition can be sterilized. Sterilizationcan be achieved by filter sterilization, autoclaving, exposure toionizing radiation, for example, gamma radiation, UV irradiation, andchemical sterilization. In one embodiment, the sterile composition has asterility assurance level of at least about 10³. The resulting liquidcompositions preferably are stable at room temperature, such that lessthan 5%, 4%, 3%, 2% or 1% by weight of the therapeutic agent degradesafter storage for 30 days, or more preferably 6 months, at 20° C.

In addition, the formulations may also include a sweetener or flavoringagent. Exemplary sweeteners or flavoring agents include, for example,acacia syrup, acesulfame potassium, anethole, anise oil, aromaticelixir, aspartame, benzaldehyde, benzaldehyde elixir, cyclodextrins,caraway, caraway oil, cardamom oil, cardamom seed, cardamom spirit,cardamom tincture, cherry juice, cherry syrup, cinnamon, cinnamon oil,cinnamon water, citric acid, citric acid syrup, clove oil, cocoa, cocoasyrup, coriander oil, dextrose, eriodictyon, eriodictyon fluid extract,eriodictyon syrup, aromatic, ethylacetate, ethyl vanillin, fennel oil,ginger, ginger fluid extract, ginger oleoresin, glucose, sugar,maltodextrin, glycerin, glycyrrhiza, glycyrrhiza elixir, glycyrrhizaextract, glycyrrhiza extract pure, glycyrrhiza fluid extract,glycyrrhiza syrup, honey, iso-alcoholic elixir, lavender oil, lemon oil,lemon tincture, maltodextrin, maltose, mannitol, methyl salicylate,menthol, nutmeg oil, orange bitter, elixir, orange bitter, oil, orangeflower oil, orange flower water, orange oil, orange peel, bitter, orangepeel sweet, tincture, orange spirit, orange syrup, peppermint,peppermint oil, peppermint spirit, peppermint water, phenylethylalcohol, raspberry juice, raspberry syrup, rosemary oil, rose oil, rosewater, saccharin, saccharin calcium, saccharin sodium, sarsaparillasyrup, sarsaparilla compound, sorbitol solution, spearmint, spearmintoil, sucrose, sucralose, syrup, thyme oil, tolu balsam, tolu balsamsyrup, wintergreen oil, vanilla, vanilla tincture, vanillin, wild cherrysyrup, xylitol, or combinations thereof.

In addition, the formulations optionally can contain a taste maskingagents. Exemplary masking agents include, for example, cyclodextrins,cyclodextrin emulsions, cyclodextrin particles, cyclodextrin complexes,or combinations thereof.

The foregoing list of excipients and additives is by no means complete,and it is understood that a person of ordinary skill in the art canchoose other excipients and additives from the GRAS (generally regardingas safe) list of chemicals used in pharmaceutical preparations and thosethat are currently allowed in topical and parenteral formulations.

Exemplary liquid compositions of the invention contain, for example, theactive ingredient (for example, midazolam), 40% (v/v) to 70% (v/v)methoxy-polyethylene glycol (for example, mPEG 350), 0% (v/v) to 20%(v/v) polyethylene glycol (for example, PEG 400), 0% (v/v) to 10% (v/v)propylene glycol, and 0% (v/v) to 5% (v/v) ethanol. Other exemplaryliquid compositions of the invention contain, for example, the activeingredient dissolved in 50% (v/v) to 70% (v/v) mPEG 350, 1% (v/v) to 4%(v/v) propylene glycol, and 1% (v/v) to 4% (v/v) ethanol.

It is understood that the choice and amounts of each of the therapeuticagents, alkoxy-polyethyline glycol and other excipients combined toproduce the compositions of the invention will depend upon the ultimateuse of the composition, and the intended therapy and mode ofadministration. When the liquid compositions ultimately are administeredto a patient, the amount of a given excipient, unless the circumstancesdictate otherwise, preferably is limited to a bioacceptable amount,which is readily determined by one of skill in the art. Furthermore, itis understood that the liquid compositions of the invention can beformulated using techniques known to those skilled in the art. Athorough discussion of formulations and the selection ofpharmaceutically acceptable carriers, stabilizers, etc. can be found,for example, in Remington's Pharmaceutical Sciences (18^(th) Ed.), MackPublishing Company, Eaton, Pa.

Although the therapeutic agent and the alkoxy-polyethylene glycol arecombined in the liquid formulations of the invention, they are notcovalently linked to one another. In certain embodiments, the liquidformulations of the invention are free or are substantially free ofchitosan. In certain embodiments, the compositions of the invention maybe prepared in a powder form.

II Modes of Administration and Pharmacokinetics

The compositions of the invention are particularly useful in deliveringone or more therapeutic agents to a mucosal membrane or the skin of amammal, for example, a human. The mucosal membrane to which thepharmaceutical preparation of the invention is administered may be anymucosal membrane of the mammal to which the therapeutic agent is to beapplied, for example, the nose (for example, via a nasal membrane),vagina, eye (for example, via an ocular membrane), ear (for example, viaa tympanic membrane), mouth (for example, via the buccal membrane),lungs (for example, via the pulmonal membrane), or rectum (for example,via the rectal membrane). The compositions are particularly useful indelivering a therapeutic agent to the mucosa of the nose, mouth (buccal,gingual, sublingual or to the hard palate), or the vagina.

It is understand that the compositions of the invention are particularlyuseful in the intranasal delivery of a therapeutic agent. When thecomposition is applied to the nasal mucosa, the volume of thepharmaceutical composition applied typically is in the range of 1-1000μL, preferably not more than 700 μL, more preferably 50-150 μL pernostril, and most preferably about 100 μL/nostril.

It is understood that when administered intranasally, the compositionsare delivered via a spray device that produces a plume of spray dropletsthat contact the nasal mucosa. It is contemplated that the compositionscan be delivered using commercially available spray devices availablefrom, for example, Pfeiffer of America, Princeton, N.J.; Valois ofAmerica, Inc., Greenwich, Conn.; or Becton Dickinson, Franklin Lakes,N.J. Furthermore, these devices are easily operable by the patient orcare giver, and leave little or no residual formulation in the deviceafter use.

Such devices can be filled with single or multi-dose amounts of thedesired formulation. The container holding the pharmaceuticalcomposition and its sealing means are sterilizable. At least the partsof the device that are in contact with the pharmaceutical compositionshould be constructed and assembled in a configuration that can besterilized. Exemplary delivery devices with one or more unit-dose(s) aredescribed, for example, in U.S. Pat. Nos. 4,946,069; 5,307,953;6,948,492; and 6,446,839. Individual devices can be packaged, sterilizedand shipped; alternatively, entire shipping and storage packages can besterilized at once, and the devices removed individually for dispensing,without affecting the sterility of the remaining units.

The mucosal epithelium in the nasal cavity is covered with manyhair-like cilia that provide an important defense mechanism againstinhaled dust, allergens and microorganisms. The normal half-time fornon-absorbed substances administered to the nasal cavity is about 15minutes due to the mucociliary clearance removing foreign particles andexcess mucus toward the pharynx. For this reason it is preferred thatthe absorption occurs rapidly and preferably within 0.5 to 20 minutes.However, in the current invention due to bioadhesive properties of theinvention, the preferred absorption may occur within 0.5 to 300 minutes(e.g., for vaccines and biologicals), preferably between 0.5 to 60minutes (e.g., for large molecules) and more preferably between 0.5 and20 minutes, for example, within 2, 3, 4, 5, 10, 15 or 20 minutes postadministration. The composition can be formulated so that uponadministration to a subject, for example, via intranasal administrationto the subject, the therapeutic agent has a peak concentration (T_(max))in the blood of the subject within 30, 25, 20, 15, 10 8, 5, 3 or 2minutes after administration of the therapeutic agent.

In addition to administration to humans, the compositions of theinvention can be used to deliver the therapeutic agent to an animal, forexample: pets, for example, dogs, cats, rabbits, and guinea pigs; andfarm animals, for example, horses, sheep, pigs, cattle, and chickens.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where processes are described as having,including, or comprising specific process steps, the processes alsoconsist essentially of, or consist of, the recited processing steps.Except where indicated otherwise, the order of steps or order forperforming certain actions are immaterial so long as the inventionremains operable. Moreover, unless otherwise noted, two or more steps oractions may be conducted simultaneously.

EXAMPLES

The invention is explained in more detail with reference to thefollowing Examples, which are to be considered as illustrative and notto be construed so as to limit the scope of the invention as set forthin the appended claims.

Example 1 Exemplary Lorazapam Containing Formulation

In this Example, 10 mg lorazepam is dissolved in 2 mL of mPEG 350 usingultrasound to obtain a solution containing 5 mg/mL of lorazepam. 50 μLof the resulting composition is administered into each nasal cavity ofmale New Zealand White rabbits held in a supine position during, andthen one minute after application. An Eppendorf pipette is used for eachapplication. After administration, blood samples then are harvested froma marginal ear vein at 0, 2, 5, 10, 15, 30 and 60 minutes, and thelorazepam concentration determined by high performance liquidchromatography (HPLC). The pharmacokinetics of lorazepam delivery viaintranasal administration can then be compared with the pharmacokineticsof lorazepam delivery by intravenous administration. It is contemplatedthat the pharmacokinetics of the intranasally administered lorazepamwill be comparable to those of the intravenously administered lorazepam.

Example 2 Exemplary Midazolam Containing Formulation

In this Example, 10 mg of midazolam is dissolved in 2 mL of mPEG 350using ultrasound to obtain a solution containing 5 mg/mL midazolam. 50μL of the resulting composition is then administered into each nasalcavity of male New Zealand White rabbits, held in a supine positionduring, and then one minute after application. After administration,blood samples then are harvested from a marginal ear vein at 0, 2, 5,10, 15, 30 and 60 minutes, and the midazolam concentration determined byHPLC. The pharmacokinetics of midazolam delivery via intranasaladministration can then be compared with the pharmacokinetics ofmidazolam delivery by intravenous administration. It is contemplatedthat the pharmacokinetics of the intranasally administered midazolamwill be comparable to those of the intravenously administered midazolam.

Example 3 Pharmacokinetics of Exemplary Midazolam Formulations

This Example describes a variety of formulations containingmethoxy-polyethylene glycol that demonstrate comparable pharmacokineticproperties to a control formulation containing polyethylene glycol andpropylene. In addition to having comparable pharmacokinetic properties,the methoxy-polyethylene glycol formulations had a lower viscosity thanthe control formulation.

Table 1 lists the composition of a first test formulation, Table 2 liststhe composition of a second test formulation, and Table 3 lists thecomposition of a control formulation.

TABLE 1 Test Formulation 1 Containing 50 mg/mL Midazolam base Percent ofFinal Component (% v/v) mPEG 350 47 PEG 400 18 Propylene Glycol 5Ethanol 7 Water 21

TABLE 2 Test Formulation 2 Containing 50 mg/mL Midazolam base Percent ofFinal Component (% v/v) mPEG 350 47 PEG 400 18 Propylene Glycol 10Polysorbate 80 0.1 Water 22

TABLE 3 Control Containing 50 mg/mL Midazolam base Percent of FinalComponent (% v/v) PEG 400 18 Propylene Glycol 78 Butylatedhydoxytoluene0.01

Each of the test and control formulations contained 50 mg/mL midazolam.Once made, 5 mg of midazolam in 0.1 mL was delivered intranasally to theright nostril of each dog (3 dogs per set) for each formulation in across over manner. Blood was harvested from the dogs predose and at0.03, 0.08, 0.16, 0.25, 0.5, 0.75, 1, 2, and 4 hours afteradministration, and the concentration of midazolam in the blood measuredby HPLC. The pharmacokinetic properties are summarized in Table 4.

TABLE 4 Pharmacokinetic Properties AUC_(last) AUC_(INF) FormulationT_(max) (hr) C_(max) (ng/mL) (hr * ng/mL) (hr * ng/mL) Test 0.11 ± 0.052220 ± 289 506 ± 94 508 ± 95 Formulation 1 Test 0.05 ± 0.03 1880 ± 682399 ± 75 403 ± 76 Formulation 2 Control 0.07 ± 0.03 2350 ± 796 506 ± 72509 ± 71 Formulation In Table 4, C_(max) refer to the maximum plasmaconcentration, T_(max) refers to the time to reach C_(max), AUC_(last)refers to area under the concentration curve from time zero to the lastmeasurable plasma concentration, and AUC_(INF) refers to the area underthe concentration curve from time zero to infinity.

The results demonstrate that the test formulations, when administeredintranasally to the dogs, produced comparable pharmacokinetics to thecontrol formulation. The test formulations, however, had a lowerviscosity than the control formulations. Lower viscosity correlates withbetter spray pattern characteristics.

Example 4 Additional Exemplary Methoxy-Polyethylene Glycol ContainingFormulations

This example describes the benefit of incorporating methoxy-polyethyleneglycol into certain intranasal formulations. Table 5 describes aformulation containing methoxy-polyethylene glycol and PEG 400, Table 6describes a formulation containing methoxy-polyethylene glycol withoutPEG 400, Table 7 describes a formulation containing methoxy-polyethyleneglycol without PEG 400 (with reduced ethanol), and Table 8 describes acontrol formulation containing PEG 400 but no methoxy-polyethyleneglycol.

TABLE 5 Component Viscosity (cP) % (w/w) Propylene glycol 40 5 PEG 40080 18 mPEG 350 29 47 Ethanol — 6 Water  1 18 Midazolam — 7

TABLE 6 Component Viscosity (cP) % (w/w) Propylene glycol 40 2 mPEG 35029 64 Ethanol — 5 Water  1 23 Midazolam — 7

TABLE 7 75 mg 50 mg 25 mg Midazolam/dose Midazolam/dose Midazolam/doseComponent (% w/w) (% w/w) (% w/w) MPEG 350 64.8 64.8 64.8 Propylene 2.02.0 2.0 glycol Ethanol 2.5 2.5 2.5 Water 23.7 26.0 28.3 Phenethyl 0.0250.025 0.025 Alcohol Midazolam 6.9 4.6 2.3

TABLE 8 Control Formulation (Without Methoxy-polyethylene Glycol)Component Viscosity (cP) % (w/w) PEG 400 89 19 Propylene Glycol 40 76Butylatedhydroxytoluene — 0.01 Midazolam — 5

The formulation of Table 5 was prepared by mixing the propylene glycol,PEG 400, mPEG 350, and ethanol. The midazolam was then added to themixture, and then after the midazolam had dissolved following mixing thewater was added to the formulation. The formulations in Tables 6 and 7were prepared as follows. The midazolam was weighed in a container andthe ethanol was added to wet the active ingredient. After mixing, about65% of the mPEG 350 was added, and the resulting mixture mixed for 2minutes. Thereafter, the additional organic phase was added. Theremaining 35% of the mPEG 350 was mixed with water, and the diluted mPEG350 then was gradually added with mixing to the midazolam solution untila clear solution was produced. The viscosity of the resultingformulations and spray patterns were tested.

The viscosity of the resulting formulations was tested at 25° C. using aviscometer (Brookfield DV-II PRO). The viscosity of the controlformulation without methoxy-polyethylene glycol (Table 8) was found tobe about 42 cP, whereas the viscosity of the test formulation of Table 5was found to be about 30 cP, and the viscosity of the test formulationof Table 6 was found to be about 23 cP. The reduced viscosity of thetest formulations relative to the control formulation permitted thecreation of more reproducible spray patterns.

The spray patterns produced by the two test formulations of Tables 5 and6 were tested using a Proveris spray view instrument. The resultingparameters of the resulting spray patterns were found to be morereproducible as the viscosity of the formulation decreased.

In addition, 100 μL of placebo formulations (no midazolam) correspondingto the formulations set forth in Tables 7 and 8 were administeredintranasally to three healthy test subjects using a commerciallyavailable spray device from Pfeiffer. The placebo formulationcorresponding to Table 7 containing methoxy-polyethylene glycol had aless noticeable taste relative to the placebo formulation correspondingto Table 8.

These collective results demonstrate that mPEG 350 is a suitableexcipient for nasal administration, for example, with midazolam.

Example 5 Sprayability of Methoxy-Polyethylene Glycol ContainingFormulations

This Example demonstrates that methoxy-polyethylene glycol-basedformulations produce superior spray flumes relative to polyethyleneglycol. Solutions containing 100% methoxy-polyethylene glycol 350 (MPEG350) from Sigma-Aldrich Chemie GmbH (St. Louis, Mo., USA) and 100%polyethylene glycol 300 (PEG 300) from Croda Chemicals Europe Ltd.(Goole, UK) were placed into Pfeiffer 20 mL bottles (Pfeiffer 34473) andattached to certain pumps from Valois or Pfeiffer (see Table 8). Eachspray device was placed 25 cm under a sheet of absorbent paper and thesprayability was measured as the diameter across of the paper wetted bythe resulting spray. The results are summarized in Table 9.

TABLE 9 Pump Type Formulation Spray diameter (cm) Pfeiffer 71514 PEG 3002.0-3.2 cm Pfeiffer 71514 mPEG 350   22-26 cm Valois VP6/100 PEG 3005.0-7.5 cm Valois VP6/100 mPEG 350   15-21 cm

The results show that there is a clear difference in the sprayability ofmPEG 350 compared with PEG 300. The required spray angle is not achievedusing PEG 300, whereas a clinically relevant spray-angle can be achievedusing mPEG 350.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A liquid pharmaceutical composition comprising a therapeutic agentand an alkoxy-polyethylene glycol represented by Formula I:R—O—(CH₂CH₂O)_(n)—H  (I) wherein: R is methyl, ethyl, n-propyl,isopropyl, or cyclopropyl; and n is a number in the range of from about1 to about
 25. 2. The pharmaceutical composition of claim 1, wherein thetherapeutic agent is an organic compound having a molecular weight ofless than 1500 g/mol.
 3. A liquid pharmaceutical composition comprisinga poorly soluble therapeutic agent and an alkoxy-polyethylene glycolrepresented by Formula I:R—O—(CH₂CH₂O)_(n)—H  (I) wherein: R is (C₁-C₆)alkyl; and n is a numberin the range of from about 1 to about
 25. 4. The pharmaceuticalcomposition of claim 1, wherein the alkoxy-polyethylene glycol comprisesfrom about 0.5% (v/v) to about 70% (v/v) of the composition.
 5. Thepharmaceutical composition of claim 1, wherein the alkoxy-polyethyleneglycol comprises about 1% (v/v) to about 60% (v/v) of the composition.6. The pharmaceutical composition of claim 1, wherein thealkoxy-polyethylene glycol comprises about 5% (v/v) to about 50% (v/v)of the composition.
 7. The pharmaceutical composition of claim 1,wherein the therapeutic agent comprises about 0.001% (w/v) to about 20%(w/v) of the composition.
 8. The pharmaceutical composition of claim 1,wherein the therapeutic agent comprises about 0.1% (w/v) to about 10%(w/v) of the composition.
 9. The pharmaceutical composition of claim 1,further comprising water.
 10. The pharmaceutical composition of claim 9,wherein the water comprises about 10% (v/v) to about 95% (v/v) of thecomposition.
 11. The pharmaceutical composition of claim 1, furthercomprising a buffer.
 12. The pharmaceutical composition of claim 1,further comprising a preservative.
 13. The pharmaceutical composition ofclaim 1, wherein the composition at a temperature of 20° C. has aviscosity in the range of from about 1.5 cP to about 60 cP.
 14. Thepharmaceutical composition of claim 1, wherein the composition at atemperature of 20° C. has a viscosity in the range of from about 5 cP toabout 25 cP.
 15. The pharmaceutical composition of claim 1, wherein thecomposition has a pH in the range of from about 4.5 to about 8.5. 16.The pharmaceutical composition of claim 1, wherein the composition has apH in the range of from about 5.5 to about 7.5.
 17. The pharmaceuticalcomposition of claim 1, wherein the composition is sterile.
 18. Thepharmaceutical composition of claim 1, wherein the composition has asterility assurance level of at least about 10³.
 19. The pharmaceuticalcomposition of claim 1, wherein less than 1% by weight of thetherapeutic agent degrades after storage for 30 days at 20° C.
 20. Thepharmaceutical composition of claim 1, wherein less than 1% by weight ofthe therapeutic agent degrades after storage for 6 months at 20° C. 21.The pharmaceutical composition of claim 1, wherein the composition isformulated so that upon intranasal administration to a subject, thetherapeutic agent has a peak concentration (t_(max)) in the blood of thesubject within 30 minutes after administration of the therapeutic agent.22. The pharmaceutical composition of claim 1, wherein the compositionis formulated so that upon intranasal administration to a subject, thetherapeutic agent has a peak concentration (t_(max)) in the blood of thesubject within 10 minutes after administration of the therapeutic agent.23. The pharmaceutical composition of claim 1, wherein R is methyl. 24.The pharmaceutical composition of claim 1, wherein n is 3-15.
 25. Thepharmaceutical composition of claim 1, wherein the alkoxy-polyethyleneglycol is mPEG 350, mPEG 550, or a combination thereof.
 26. Thepharmaceutical composition of claim 1, wherein the alkoxy-polyethyleneglycol is methoxy-triethylene glycol (m3EG), methoxy-tetraethyleneglycol (m4EG), methoxy-pentaethylene glycol (m5EG), methoxy-hexaethyleneglycol (m6EG), methoxy-heptaethylene glycol (m7EG), methoxy-octaethyleneglycol (m8EG), methoxy-nonaethylene glycol (m9EG), methoxy-decaethyleneglycol (m10EG), methoxy-undecaethylene glycol (m11EG),methoxy-dodecaethylene glycol (m12EG), methoxy-tridecaethylene glycol(m13EG), or methoxy-tetradecaethylene glycol (m14EG).
 27. Thepharmaceutical composition of claim 1, wherein the therapeutic agent hasa molecular weight of less than 500 g/mol.
 28. The pharmaceuticalcomposition of claim 1, wherein the therapeutic agent has an aqueoussolubility of less than about 0.3 mg/mL at pH 7 and 20° C.
 29. Thepharmaceutical composition of claim 1, wherein the therapeutic agent hasan aqueous solubility of less than about 0.1 mg/mL at pH 7 and 20° C.30. The pharmaceutical composition of claim 1, wherein the therapeuticagent is a benzodiazepine.
 31. The pharmaceutical composition of claim30, wherein the therapeutic agent is midazolam.
 32. (canceled)
 33. Amethod of administering a therapeutic agent to a mammal, the methodcomprising administering a pharmaceutical composition of claim 1 to amucosal surface of the mammal.
 34. The method of claim 33, wherein themucosal surface is a nasal membrane, sublingual membrane, buccalmembrane, pulmonal membrane, ocular membrane, or rectal membrane. 35.The method of claim 33, wherein the mucosal surface is a nasal membrane.36. The method of claim 33, wherein the therapeutic agent has a peakconcentration (T_(max)) in the blood of the mammal within 30 minutesafter administration of the therapeutic agent.
 37. The method of claim33, wherein the therapeutic agent has a peak concentration (T_(max)) inthe blood of the mammal within 10 minutes after administration of thetherapeutic agent.
 38. The method of claim 33, wherein thepharmaceutical composition is administered in a volume of from about 1μL to about 1000 μL.
 39. The method of claim 38, wherein thepharmaceutical composition is administered in a volume from about 50 μLto about 300 μL.
 40. The method of claim 33, wherein the mammal is ahuman.